Companion diagnostics are medical devices which provide information that is essential for the safe and effective use of a corresponding drug facilitating personalized therapies in which treatment can be customized for an individual patient. It is reasonable to combine drug and companion diagnostic development, however, co-development programs must overcome regulatory hurdles and additional complexity until marketing authorization approval.

The development program of Pembrolizumab is an example for the successful co-development of a new biological drug accompanied by a companion diagnostic. Michael Firgens summarizes several lessons from the co-development of Pembrolizumab and its companion diagnostic that can be considered for future co-development programs of medicinal products.

Companion diagnostics are medical devices which provide information that is essential for the safe and effective use of a corresponding drug or biological product. They are used to identify and help direct therapies to patients who are most likely to experience a favourable benefit risk outcome with a selected medicinal product. Therefore, they facilitate personalized therapies in which treatment can be customized for an individual patient. For example in cancer, specific information about a patient’s tumour can be used to help to diagnose, to plan the treatment, to find out how well the treatment is working, or to make a prognosis. Consequently, it is reasonable to combine drug and companion diagnostic development. However, co-development programs must overcome regulatory hurdles and additional complexity until marketing authorization approval.

The development program of Pembrolizumab is an example for the successful co-development of a new biological drug accompanied by a companion diagnostic, which obtained accelerated approval for different indications and the approval of a companion diagnostic. Pembrolizumab is commercialized by Merck & Co. under the tradename Keytruda. The drug is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, thereby enabling an antitumor immune response. The clinical development began in 2010, and accelerated approval for Pembrolizumab was granted by FDA in 2014. The development program of Pembrolizumab is summarized in Figure 1. Along with the drug development, an immunohistochemistry (IHC) assay for PD-L1 expression was developed as companion diagnostic (Dako IHC 22C3 pharmDx). The test was developed to identify PD-L1 positive tumors in patients with NSCLC. The authorized indications of Pembrolizumab were successively extended. Recently, FDA granted approval for the use of Pembrolizumab in patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, which aims at treating a condition based on a specific biomarker rather than a specific tumor type.

There are several lessons from the co-development of Pembrolizumab and its companion diagnostic that can be considered for future co-development programs of medicinal products such as:

1. A predictive biomarker was established to accurately identify patients who will benefit from anticancer treatment, i.e. PD-L1 in NSCLC and melanoma.

2. To facilitate treatment guidance, a clear threshold of the test assay has been defined. PD-L1 protein expression in NSCLC is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The specimen should be considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%.

3. Training and validation sets of the PD-L1 IHC companion diagnostic were part of an integrated strategy in the clinical development program.

4. In contrast to the traditional development path, the clinical development program of Pembrolizumab utilized an adaptive trial design. KEYNOTE-001 was composed of nested phase-2-like studies in two oncologic indications, i.e. melanoma and NSCLC, with six randomized dose/schedule-comparison sub-studies involving both patient populations. The implementation of multiple expansion cohorts into the trial design allowed to address multiple hypotheses and to evaluate different tumor types simultaneously.

5. The biology of the biomarker and the drug’s mechanism of action were adequately understood to guide the development of the companion diagnostic and to pursue the authorization of biomarker specific indications.

Biopharma Excellence is experienced in the development of biological drugs and companion diagnostics in the EU and the US. We understand the unique challenges of co-development programs and how to solve them. Please contact us to learn more.